Tauopathies are a class of age-related neurodegenerative diseases that millions of people in our country suffer from today. Tauopathies are characterized by the abnormal accumulation of tau, a microtubule- associated protein, in the brain which is linked to severe and debilitating cognitive dysfunction. There are currently a limited number of treatment options available for people suffering from tauopathy and there is no cure. Research to identify the mechanisms for the pathogenic effect of tau is crucial to find new molecular targets for drug intervention. Recent evidence suggests that acetylated tau (ac-tau) may contribute to pathogenesis in tauopathy, however whether ac-tau affects neuronal function underlying cognitive impairments is unknown. My long-term goal is to uncover the role of ac-tau in neurodegenerative tauopathy to provide a foundation for targeting ac-tau as a novel strategy to treat cognitive dysfunction. Aim 1 is to determine how ac-tau affects excitatory synaptic physiology in the hippocampus. Human tau constructs with lysines mutated to glutamines to mimic acetylation at specific residues (K/Q mutants) will be expressed in mouse hippocampal neurons in vivo by lentiviral-based gene transfer. Electrophysiological recordings will be performed on neurons to examine the postsynaptic effect of K/Q mutants on basal excitatory transmission and synaptic plasticity. Preliminary results from recordings of cultured neurons show that a K/Q mutant in the microtubule-binding domain of tau causes a reduction in glutamatergic synaptic transmission. Aim 2 is to determine the molecular mechanism for the effect of ac-tau on excitatory postsynaptic function. Immunocytochemistry and confocal microscopy will be used to investigate whether ac-tau is aberrantly localized at excitatory synapses in dendritic spines. Furthermore, immunostaining of postsynaptic glutamate receptors will be done to examine how the K/Q mutants modulate receptors leading to synaptic dysfunction. This will be followed by an investigation of a specific molecular interaction linking ac-tau to the regulation of postsynaptic glutamate receptors. Aim 3 is to establish the pathogenic effect of ac-tau in vivo. A transgenic mouse will be generated with neuronal expression of a human tau K/Q mutant that causes synaptic pathophysiology (tau-K/Q mice). Any abnormal modifications of the functional circuitry in the hippocampus of tau-K/Q mice will be monitored by electrophysiological recordings of excitatory synaptic transmission and synaptic plasticity. Behavioral tests will determine if tau-K/Q mice develop deficits in learning and memory associated with tauopathies. Finally, histological and biochemical analyses will be performed on aged tau-K/Q mice to evaluate neurodegeneration and tau pathology in the brain. Together, the results from this project will provide significant insight into the pathogenic mechanisms of tau in neurodegenerative disease.